Antidepressant Use During Pregnancy

Beena N. Patel; Janalynn Beste; Jean C. Blackwell

May 15, 2011 Issue

FPIN's Clinical Inquiries

Antidepressant Use During Pregnancy

BEENA N. PATEL, DO, and JANALYNN BESTE, MD, New Hanover Regional Medical Center Family Medicine Residency Program, Wilmington, North Carolina

JEAN C. BLACKWELL, MLS, University of North Carolina at Chapel Hill Health Sciences Library, Chapel Hill, North Carolina

Am Fam Physician. 2011 May 15;83(10):1211-1215.

Clinical Question

Which antidepressants are safe to use during pregnancy?

Evidence-Based Answer

There are no studies that have shown any antidepressant to be absolutely safe for use during any stage of pregnancy. The use of selective serotonin reuptake inhibitors (SSRIs) or tricyclic antidepressants (TCAs) during pregnancy does not increase the risk of congenital malformations or miscarriage. (Strength of Recommendation [SOR]: B, based on limited-quality, patient-oriented evidence.) The use of SSRIs or TCAs during pregnancy may increase the risk of preterm birth, low birth weight, respiratory distress, and neonatal convulsions, without obvious subsequent adverse neurodevelopmental outcomes. (SOR: B, based on limited-quality, patient-oriented evidence.) Table 11–8 lists reported outcomes and corresponding risks of antidepressant use during pregnancy.

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Table 1.

Reported Outcomes of Antidepressant Use During Pregnancy

Drug	Study type	Outcome	Risk
Tricyclic antidepressants
Amitriptyline and nortriptyline (Pamelor)	Case-control study1	No increased risk of major congenital malformations	OR = 0.78
	Case-control study1	No increased risk of major congenital malformations	95% CI, 0.30 to 2.02
	Structured blind review2	No increased risk of major congenital malformations	OR = 0.82
		No increased risk of major congenital malformations	95% CI, 0.35 to 1.95
		No increased risk of developmental delay	OR = 1.00
		No increased risk of developmental delay	95% CI, 0.14 to 7.17
	Prospective case-control study3	Increased risk of preterm birth	OR = 2.50
		Increased risk of preterm birth	95% CI, 1.87 to 3.34
		Increased risk of low birth weight	OR = 1.88
		Increased risk of low birth weight	95% CI, 1.28 to 2.76
		Increased risk of respiratory distress	OR = 2.20
		Increased risk of respiratory distress	95% CI, 1.44 to 3.35
		Increased risk of hypoglycemia	OR = 2.07
		Increased risk of hypoglycemia	95% CI, 1.36 to 3.13
		Increased risk of low Apgar score	OR = 2.99
		Increased risk of low Apgar score	95% CI, 1.58 to 5.65
		Increased risk of convulsions	OR = 6.8
		Increased risk of convulsions	95% CI, 2.2 to 16.0
Selective serotonin reuptake inhibitors
Citalopram (Celexa)	Prospective case-control study4	No increased risk of major congenital malformations	0.9 percent in exposed group vs. 2.6 percent in control group
		No increased risk of major congenital malformations	P = .64
		Increased risk of admission to neonatal intensive care unit	RR = 4.2
		Increased risk of admission to neonatal intensive care unit	95% CI, 1.71 to 10.26
Fluoxetine (Prozac)	Structured blind review2	No increased risk of major congenital malformations	OR = 1.36
		No increased risk of major congenital malformations	95% CI, 0.56 to 3.30
		No increased risk of minor congenital malformations	OR = 1.14
		No increased risk of minor congenital malformations	95% CI, 0.56 to 2.31
	Prospective controlled cohort study5	No increased risk of miscarriage	RR = 1.9
		No increased risk of miscarriage	95% CI, 0.92 to 3.92
		No increased risk of major congenital malformations	2 percent in exposed group vs. 1.8 percent in control group
		No increased risk of major congenital malformations	P = .38
	Prospective case-control study6	Increased risk of preterm birth	RR = 4.8
		Increased risk of preterm birth	95% CI, 1.1 to 20.8
		Increased risk of poor neonatal adaptation, including respiratory difficulty, jitteriness, and cyanosis with feedings	RR = 8.7
			95% CI, 2.9 to 26.6
Paroxetine (Paxil)	Case-control study1	No increased risk of major congenital malformations	OR = 1.27
	Case-control study1	No increased risk of major congenital malformations	95% CI, 0.78 to 2.06
	Case-control study 7	No increased risk of cardiovascular defects	OR = 1.10
	Case-control study 7	No increased risk of cardiovascular defects	95% CI, 0.36 to 2.78
Sertraline (Zoloft)	Structured blind review2	No increased risk of major congenital malformations	OR = 1.36
Sertraline (Zoloft)	Structured blind review2	No increased risk of major congenital malformations	95% CI, 0.56 to 3.30
Venlafaxine (Effexor)	Prospective controlled study8	No increased risk of major congenital malformations	1.6 percent in exposed group vs. 0.7 percent in control group
Venlafaxine (Effexor)	Prospective controlled study8	No increased risk of major congenital malformations	P = .93

CI = confidence interval; OR = odds ratio; RR = relative risk.

Information from references 1 through 8.

Table 1.

Reported Outcomes of Antidepressant Use During Pregnancy

Drug	Study type	Outcome	Risk
Tricyclic antidepressants
Amitriptyline and nortriptyline (Pamelor)	Case-control study1	No increased risk of major congenital malformations	OR = 0.78
	Case-control study1	No increased risk of major congenital malformations	95% CI, 0.30 to 2.02
	Structured blind review2	No increased risk of major congenital malformations	OR = 0.82
		No increased risk of major congenital malformations	95% CI, 0.35 to 1.95
		No increased risk of developmental delay	OR = 1.00
		No increased risk of developmental delay	95% CI, 0.14 to 7.17
	Prospective case-control study3	Increased risk of preterm birth	OR = 2.50
		Increased risk of preterm birth	95% CI, 1.87 to 3.34
		Increased risk of low birth weight	OR = 1.88
		Increased risk of low birth weight	95% CI, 1.28 to 2.76
		Increased risk of respiratory distress	OR = 2.20
		Increased risk of respiratory distress	95% CI, 1.44 to 3.35
		Increased risk of hypoglycemia	OR = 2.07
		Increased risk of hypoglycemia	95% CI, 1.36 to 3.13
		Increased risk of low Apgar score	OR = 2.99
		Increased risk of low Apgar score	95% CI, 1.58 to 5.65
		Increased risk of convulsions	OR = 6.8
		Increased risk of convulsions	95% CI, 2.2 to 16.0
Selective serotonin reuptake inhibitors
Citalopram (Celexa)	Prospective case-control study4	No increased risk of major congenital malformations	0.9 percent in exposed group vs. 2.6 percent in control group
		No increased risk of major congenital malformations	P = .64
		Increased risk of admission to neonatal intensive care unit	RR = 4.2
		Increased risk of admission to neonatal intensive care unit	95% CI, 1.71 to 10.26
Fluoxetine (Prozac)	Structured blind review2	No increased risk of major congenital malformations	OR = 1.36
		No increased risk of major congenital malformations	95% CI, 0.56 to 3.30
		No increased risk of minor congenital malformations	OR = 1.14
		No increased risk of minor congenital malformations	95% CI, 0.56 to 2.31
	Prospective controlled cohort study5	No increased risk of miscarriage	RR = 1.9
		No increased risk of miscarriage	95% CI, 0.92 to 3.92
		No increased risk of major congenital malformations	2 percent in exposed group vs. 1.8 percent in control group
		No increased risk of major congenital malformations	P = .38
	Prospective case-control study6	Increased risk of preterm birth	RR = 4.8
		Increased risk of preterm birth	95% CI, 1.1 to 20.8
		Increased risk of poor neonatal adaptation, including respiratory difficulty, jitteriness, and cyanosis with feedings	RR = 8.7
			95% CI, 2.9 to 26.6
Paroxetine (Paxil)	Case-control study1	No increased risk of major congenital malformations	OR = 1.27
	Case-control study1	No increased risk of major congenital malformations	95% CI, 0.78 to 2.06
	Case-control study 7	No increased risk of cardiovascular defects	OR = 1.10
	Case-control study 7	No increased risk of cardiovascular defects	95% CI, 0.36 to 2.78
Sertraline (Zoloft)	Structured blind review2	No increased risk of major congenital malformations	OR = 1.36
Sertraline (Zoloft)	Structured blind review2	No increased risk of major congenital malformations	95% CI, 0.56 to 3.30
Venlafaxine (Effexor)	Prospective controlled study8	No increased risk of major congenital malformations	1.6 percent in exposed group vs. 0.7 percent in control group
Venlafaxine (Effexor)	Prospective controlled study8	No increased risk of major congenital malformations	P = .93

CI = confidence interval; OR = odds ratio; RR = relative risk.

Information from references 1 through 8.

Evidence Summary

Data on antidepressant use during pregnancy are limited to retrospective studies and medication registries because of a lack of randomized controlled trials.

TRICYCLIC ANTIDEPRESSANTS

A case-control study found that TCA use during the first trimester was not associated with an increased risk of major congenital malformations.1

A structured blind review of 209 medical records also found no association between TCA use and major congenital malformations or developmental delay.2 A study using a birth registry that included 395 infants exposed to TCAs found an increased risk of preterm birth, low birth weight, respiratory distress, hypoglycemia, low Apgar score, and convulsions.3 A prospective study of 80 mothers taking TCAs found that in utero exposure does not affect global IQ, language development, or behavioral development in children 16 to 86 months of age.9

SELECTIVE SEROTONIN REUPTAKE INHIBITORS

Citalopram. A prospective case-control study of 125 women taking citalopram (Celexa) in the first trimester showed no association between citalopram use and major congenital malformations; however, use later in pregnancy is associated with an increased risk of admission to the neonatal intensive care unit.4

Fluoxetine. A prospective controlled cohort study of 128 pregnant women taking fluoxetine (Prozac) found no increased risk of major congenital malformations or difference in rates of miscarriage.5 A structured blind review of medical records of 185 pregnant women taking SSRIs, including 129 taking fluoxetine, showed no difference in rates of major or minor congenital malformations, developmental delay, or other neurologic disorders.2 A prospective case-control study found that third-trimester exposure to fluoxetine was associated with an increased risk of preterm birth, as well as poor neonatal adaptation, including respiratory difficulty, jitteriness, and cyanosis with feedings.6

Paroxetine. A case-control study using a medication and pregnancy registry that included 2,329 women found that first-trimester use of paroxetine (Paxil) was not associated with an increased risk of major congenital malformations.1 A case-control study of more than 3,000 infants with documented exposure to paroxetine during the first trimester found that rates of cardiovascular defects were 0.7 percent both in the group exposed to paroxetine and in the unexposed group.7

Sertraline. A structured blind review of medical records of 185 infants exposed to SSRIs, including 32 exposed to sertraline (Zoloft), showed no difference in rates of major congenital malformations or developmental delay.2

Venlafaxine. A prospective controlled study of 150 pregnant women taking venlafaxine (Effexor) in the first trimester concluded that the use of venlafaxine does not increase the risk of major congenital malformations.8

Little information is available on the use of duloxetine (Cymbalta), escitalopram (Lexapro), or bupropion (Wellbutrin) during pregnancy.

Recommendations from Others

The American College of Obstetricians and Gynecologists (ACOG) recommends avoiding paroxetine use during pregnancy. Fetal echocardiography should be considered if a woman takes paroxetine in early pregnancy. ACOG also recommends the use of a single medication at higher dosages over the use of multiple psychotropic medications. Treatment with SSRIs, selective norepinephrine reuptake inhibitors, or both should be individualized.10

Address correspondence to Beena N. Patel, DO, at bpatel88@hotmail.com. Reprints are not available from the authors.

Author disclosure: Nothing to disclose.

REFERENCES

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1. Ramos E, St-André M, Rey E, Oraichi D, Bérard A. Duration of antidepressant use during pregnancy and risk of major congenital malformations. Br J Psychiatr. 2008;192(5):344–350....

2. Simon GE, Cunningham ML, Davis RL. Outcomes of pre-natal antidepressant exposure. Am J Psychiatry. 2002;159(12):2055–2061.

3. Källén B. Neonate characteristics after maternal use of antidepressants in late pregnancy. Arch Pediatr Adolesc Med. 2004;158(4):312–316.

4. Sivojelezova A, Shuhaiber S, Sarkissian L, Einarson A, Koren G. Citalopram use in pregnancy: prospective comparative evaluation of pregnancy and fetal outcome. Am J Obstet Gynecol. 2005;193(6):2004–2009.

5. Pastuszak A, Schick-Boschetto B, Zuber C, et al. Pregnancy outcome following first-trimester exposure to fluoxetine (Prozac). JAMA. 1993;269(17):2246–2248.

6. Chambers CD, Johnson KA, Dick LM, Felix RJ, Jones KL. Birth outcomes in pregnant women taking fluoxetine. N Engl J Med. 1996;335(14):1010–1015.

7. Einarson A, Pistelli A, DeSantis M, et al. Evaluation of the risk of congenital cardiovascular defects associated with use of paroxetine during pregnancy [published corrections appear in Am J Psychiatry. 2008;165(9):1208 and Am J Psychiatry. 2008;165(6):777]. Am J Psychiatry. 2008;165(6):749–752.

8. Einarson A, Fatoye B, Sarkar M, et al. Pregnancy outcome following gestational exposure to venlafaxine: a multicenter prospective controlled study. Am J Psychiatry. 2001;158(10):1728–1730.

9. Nulman I, Rovet J, Stewart DE, et al. Neurodevelopment of children exposed in utero to antidepressant drugs. N Engl J Med. 1997;336(4):258–262.

10. ACOG Practice Bulletin: Clinical management guidelines for obstetrician-gynecologists number 92, April 2008 (replaces practice bulletin number 87, November 2007). Use of psychiatric medications during pregnancy and lactation. Obstet Gynecol. 2008;111(4):1001–1020.

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